Chlamydia trachomatis (CT) infection is the most prevalent bacterial sexually transmitted infection, and infection rates are highest in African Americans. CT infection causes major reproductive morbidity in women. Control measures have not diminished the epidemic; a vaccine is urgently needed. CT vaccine development has been hindered by inadequate knowledge of immunogenetic factors influencing protective immunity in humans. Murine models reveal CD4+ T helper type 1 (Th1) immune responses and Th1 chemokine receptor expression are essential for protective immunity to CT, while Th2 responses impair immunity; however, differences between animal models makes translating findings to humans challenging. Human studies reveal cellular immune responses to CT, but rarely have responses contributing to protective immunity been studied; access to well-characterized cohorts is a major obstacle. Some at risk individuals do not have CT re-infection, likely in some because immunogenetic factors mediate protection. Sparse data suggests genetic determinants influence risk for re-infection, but underlying immune pathways remain elusive. Our long range goal is to bridge gaps in knowledge of immunogenetic factors mediating protective immunity to CT in humans. Preliminary studies in a well-characterized cohort of CT-infected women revealed: 1) CT re-infection in 15% by 6 months after therapy and 2) women without re-infection more often had CT-specific Th1 responses (IFN-3 and TNF-1) and expression of Th1 chemokine receptor CCR5 and less often HLA-DQB1*05 and IL10 gene variants. Our overall hypothesis is that CT-specific systemic and mucosal Th1 cytokine responses (mainly IFN-3 and TNF-1) and chemokine responses and also expression of Th1 chemokine receptors will be associated with decreased CT re-infection risk, while select HLA class II alleles and IL10 gene variants will be associated with increased re-infection risk. Our approach to verify the hypothesis consists of three specific aims: 1) Demonstrate that CT re-infection risk is reduced in women with a CT-specific CD4+ Th1 response (mainly IFN-3 and TNF-1), 2) Determine the phenotype of systemic and mucosal T cell subsets associated with CT re- infection risk in women, and 3) Delineate and further refine associations of HLA Class II alleles and IL10 gene variants with re-infection in women. CT-infected women from a well-characterized population will be enrolled and undergo repeat CT testing at 3- and 6-month visits. Systemic and mucosal immunological studies (of CT- specific cytokine and chemokine responses and T cell phenotype distributions) as well as targeted HLA class II and IL10 gene variant typing and genetic data analyses will be carried out in subjects with and without CT re- infection. The goal of the proposal is to elucidate cellular immune responses and cell phenotypes associated with protective immunity to CT re-infection in humans, and to expand our understanding of the relationship of immune correlates with genetic variants that influence re-infection risk. Study findings should provide systemic and mucosal immune correlates of protection needed for CT vaccine studies. PUBLIC HEALTH RELEVANCE: Despite prevention and control measures, Chlamydia trachomatis infection remains the most prevalent bacterial sexually transmitted infection and causes major reproductive morbidity. The goal of the proposal is to elucidate systemic and mucosal cellular immune responses and cell phenotypes associated with protective immunity to chlamydia re-infection in humans, and expand our understanding of the influence of genetic determinants and the associated immune pathways that mediate protective immunity. Study findings should provide knowledge that can advance chlamydia vaccine development.